Arene ruthenium complex has the classical “piano stool” geometry. The arene ruthenium complex is a small molecular organometallic compound which forms a covalent bond through π-orbital electron on benzene ring and the center metal ruthenium, wherein the auxiliary ligand is benzene or substituted benzene with strong hydrophobicity. The synthesis of various types of arene ruthenium complexes and utilization thereof as an anticancer agent have been reported in a large amount of literature, both at home and abroad, since the first synthesis of arene ruthenium (II) complexes by Winkhaus and Singer in 1967.
Kondapi et al. reported that arene ruthenium complexes represented by [(η6-C6H6)Ru(DMSO)Cl2]2+ have showed good inhibitory effect on Colo-205 human colon carcinoma cells and ZR-75-1 breast cancer cells, strong affinity for DNA, and inhibiting the growth and proliferation of tumor cells by inhibiting the activity of topoisomerase II. [Vashisht G Y N, Konuru N, KondapiAK. Topoisomerase II antagonism and anticancer activity of coordinated derivatives of [RuCl2(C6H6)(dmso)]. [J]. Arch. Biochem. Biophys, 2002, 401(1):53-62].
A class of arene ruthenium (II) complexes with amantadine ligands reported by Dyson et al. were synthesized by heating and refluxing a mixture of [RuCl2(η6-arene)]2 (0.64 mmol) and PTA (1.28 mmol) in methanol solvent for 24 h with a yield of 85-95%. [Scolaro C, Bergamo A, Brescacin L, Delfino R, Cocchietto M, Laurenczy G, Geldbach T J, Sava G, Dyson P J. In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. [J]. J Med Chem, 2005, 48: 4161-4171]. This class of complexes exhibit growth inhibitory activity against TS/A cell (IC50 60˜300 μM) and low toxicity to normal human cells (IC50>300 μM). Wherein the complexes RAPTA-B ([Ru(η6-C6H6)(pta)Cl2]) and RAPTA-C([Ru(η6-p-C6H4MeiPr)(pta)Cl2]) induce G2/M phase arrest and apoptosis in cancer cells by regulating various signal pathways of mitochondrial and P53-JNK, increasing p21 level and reducing the amount of Cyclins E[Chatterjee S, Kundu S, Bhattacharyya A, Hartinger C G, Dyson P J, The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways. [J]. J Biol Inorg Chem, 2008, 13:1149-1155]. Moreover, in vivo studies showed that RAPTA-C can inhibit the proliferation and metastasis of MCa breast cancer in CBA mice through inhibiting angiogenesis [Nowak-Sliwinska P, Van B J R, Casini A. Organometa llic ruthenium(II) arene com-pounds with antiangiogenic activity[J]. J. Med. Chem. 2011, 54(11):3895-3902].
The arene ruthenium (II) complexes with ethylenediamine ligand reported by Sadler et al. were synthesized by adding [RuCl2(η6-arene)]2 (0.64 mmol) and ethylenediamine derivative (2.0 mmol) into a methanol solvent, stirring for 1.5 h, adding NH4PF6, filtrating, and recrystallizing the filtrate in fridge for 6 h. The yield was 37.7%. This type of complexes exhibit effective growth inhibitory activity against A2780 human ovarian cancer cells without cross resistance. The complexes can bind to the guanines in DNA closely, which is an important strategy to develop the targeting of antitumor activity against tumor cells [Morris R E, Aird R E, del Socorro Murdoch P, Chen H, Cummings J, Hughes N D, Parsons S, Parkin A, Boyd G, Jodrel lD I, Sadler P J. Inhibition of cancer cell growth by ruthenium (II) arene complexes. J Med Chem, 2001, 44: 3616-3621]. Wherein the complex RM175 ([(η6-biphenyl)Ru(ethylenediamine)-Cl]+) can inhibit tumor invasion and metastasis by promoting cell-cell re-adhesion and reducing the release of metalloproteinases (MMPs) [Bergamo A, Masi A, Peacock A F, Habtemariam A, Sadler P J, Sava G J. In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model. Inorg Biochem, 2010, 104:79-86], [Habtemariam A, Melchart M, Fernandez R, Parsons S, Oswald I D H, Parkin A, Fabbiani F P A, Davidson J E, Dawson A, Aird R E, Jodrell D I, Sadler P J. Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands. J. Med Chem, 2006, 49: 6858-6868].
Another type of arene ruthenium (II) complexes [(η6-arene)Ru(β-diketonate)Cl] with 2,4-pentanedione ligand reported by Sadler et al. were obtained by mixing and stirring [RuCl2 (η6-arene)] and sodium acetylacetonate in acetone for 50 min. The yield was 61.2%. The IC50 values of these complexes in the human ovarian cancer line A2780 in vitro are determined by the types of auxiliary ligands of the arene ring. The complexes with an arene ring of p-cymene ligand has a highest antitumor activity compared to those with other ligands, wherein the complex [(η6-p-cymene) Ru (β-diketonate) Cl] exhibits effective antitumor activity against the human ovarian cancer cell line A2780 with IC50 of 17 μM.
The arene ruthenium (II) complexes with carboline ligand reported by Mao et al. were obtained through refluxing [RuCl2(η6-arene)] and carboline derivative in methanol for 2.5 h. The yield was 78%. The in vitro antitumor activity of this type of complexes is 3 to 12 times higher than that of cisplatin against tumor cell lines in vitro, but much lower cytotoxic against normal cells, as well as no cross-resistance to cisplatin was found. Especially, the complexes exhibit high antitumor activity against cisplatin-resistant cell lines A549cisR, and low toxicity to normal human nonfibroblast cell lines HLF. The complexes may directly target CDK1 (cyclin-dependent kinase) by downregulating the expression of CDK1 and cyclin B1, induce G2M phase arrest block in cancer cells. Furthermore, the complexes can effectively induce apoptosis through mi-tochondrial-related pathways and increase the amount of intracellular reactive oxygen species (ROS) elevation [He L, Liao S Y, Tan C P, Ye R R, Xu Y W, Zhao M, Ji L N, Mao Z W. Ruthenium-Arene-β-Carboline Complexes as Potent Inhibitors of Cyclindependentent Kinase 1: Synthesis, Characterization and Anticancer Mechanism Studies. Chem. Eur. J, 2013, 19, 12152-12160].
Three ruthenium arene complexes with thiosemicarbazones ligand [(η6-p-cymene)Ru(R-BzTSC)Cl]Cl (BzTSC=benzaldehyde thiourea, R═H, CH3 and C6H5) reported by Su et al. were obtained through refluxing [RuCl2(η6-p-cymene)] (0.05 mmol) and benzaldehyde thiourea (0.1 mmol) in acetone for 6 h at 45° C. The yield was 39%. These types of arene ruthenium complexes exhibit effective anti-proliferative activity against nasopharyngeal carcinoma, lung cancer, breast cancer and ovarian cancer cells. Wherein the complexes [(η6-p-cymene)Ru(C6H5-BzTSC)Cl]Cl exhibit most effective anti-proliferative activity with IC50 values of 20 μM, 31 μM, 10 μM and 34 μM, respectively [Su W, Zhou Q, Huang Y M, et al. Synthesis, crystal and electronic structure, anticancer activity of ruthenium(II) arene complexes with thiosemicarbazones[J]. Appl. Organometal. Chem. 2013, 27(5): 307-312.].
Due to differences in ligands, the arene ruthenium complexes presented usually have different anticancer activities against various tumor cell lines. Therefore, specific to different tumor symptoms, developing different types of ruthenium arene complexes is necessary.